The overall use of EVAR has risen sharply in the past 10 years (5.2% to 74% of the total number of AAA repairs) even though the total number of AAAs remains stable at 45,000 cases per year. In-hospital mortality rates for both ruptured and unruptured cases have fallen by more than 50% during this time period. Lower mortality rates and shorter LOS despite a 27%-36% higher cost of care continues to justify the use of EVAR over OAR. For patients with suitable anatomy, EVAR should be the preferred management of both ruptured and unruptured AAAs.

SUMMARY Pancreatic cancer is a deadly disease characterized by late diagnosis and resistance to therapy. Much progress has been made in defining gene defects in pancreatic cancer, but a full accounting of its molecular pathogenesis awaits. Here, we show that expression of Ataxia-Telangiectasia Group D Complementing gene (ATDC), also called TRIM29, is elevated in most invasive pancreatic cancers and pancreatic cancer precursor lesions. ATDC promoted cancer cell proliferation in vitro and enhanced tumor growth and metastasis in vivo. ATDC expression correlated with elevated β-catenin levels in pancreatic cancer, and β-catenin function was required for ATDC’s oncogenic effects. ATDC was found to stabilize β-catenin via ATDC-induced effects on the disheveled-2 protein, a negative regulator of GSK3β in the Wnt/β-catenin signaling pathway. SIGNIFICANCE Pancreatic cancer is an aggressive malignancy, and an improved understanding of the molecular mechanisms governing its highly aggressive behavior is needed for more effective treatment, early detection and prevention. Defects in Wnt/β-catenin signaling are common in certain cancers, such as colorectal carcinoma, and recent evidence suggests Wnt/β-catenin signaling may contribute to pancreatic cancer. In this report, we show that ATDC is over-expressed in the majority of invasive pancreatic cancers and pancreatic cancer precursor lesions. ATDC contributes to pancreatic cancer via its ability to interact with and stabilize expression of disheveled-2, with resultant stabilization of β-catenin. Besides highlighting ATDC as a potential therapeutic target in pancreatic cancer, our studies have defined a novel mechanism for activating Wnt/β-catenin signaling in cancer.

Cellular heterogeneity in cancer was observed decades ago by studies in mice which showed that distinct subpopulations of cells within a tumor mass are capable of driving tumorigenesis. Conceptualized from this finding was the stem-cell hypothesis for cancer, which suggests that only a specific subset of cancer cells within each tumor is responsible for tumor initiation and propagation, termed tumor initiating cells or cancer stem cells (CSCs). Recent data has been provided to support the existence of CSCs in human blood cell-derived cancers and solid organ tumors of the breast, brain, prostate, colon, and skin. Study of human pancreatic cancers has also revealed a specific subpopulation of cancer cells that possess the characteristics of CSCs. These pancreatic cancer stem cells express the cell surface markers CD44, CD24, and epithelial-specific antigen, and represent 0.5% to 1.0% of all pancreatic cancer cells. Along with the properties of self-renewal and multilineage differentiation, pancreatic CSCs display upregulation of important developmental genes that maintain self-renewal in normal stem cells, including Sonic hedgehog (SHH) and BMI-1. Signaling cascades that are integral in tumor metastasis are also upregulated in the pancreatic CSC. Understanding the biologic behavior and the molecular pathways that regulate growth, survival, and metastasis of pancreatic CSCs will help to identify novel therapeutic approaches to treat this dismal disease.

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Emerging evidence suggests that malignant tumors are composed of a small subset of distinct cancer cells, termed "cancer stem cells" (typically less than 5% of total cancer cells based on cell surface marker expression), which have great proliferative potential, as well as more differentiated cancer cells, which have very limited proliferative potential. Data have been provided to support the existence of cancer stem cells in several different types of cancer, including human blood, brain, prostate, ovarian, melanoma, colon, and breast cancers. We have recently reported the identification of a subpopulation of pancreatic cancer cells that express the cell surface markers CD44+CD24+ESA+ (0.2-0.8% of all human pancreatic cancer cells) that function as pancreatic cancer stem cells. The CD44+CD24+ESA+ pancreatic cancer cells are highly tumorigenic and possess the stem cell-like properties of self-renewal and the ability to produce differentiated progeny. Pancreatic cancer stem cells also demonstrate upregulation of molecules important in developmental signaling pathways, including sonic hedgehog and the polycomb gene family member Bmi-1. Of clinical importance, cancer stem cells in several tumor types have shown resistance to standard therapies and may play a role in treatment failure or disease recurrence. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.